Oleandomycin antibiotic in feed



United States Patent O I 2,925,342 OLEANDOMYCIN ANmrorrc IN FEED WilliamC. Sherman, Gerald A. Donovan, Warren M- value inanimal growthstimulation. However, if a diseased conditionis encountered oranticipated in-the ani- Reynolds, and Herbert GILuthen'Terre'Haute,Ind.,

assignors to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation ofDelaware No Drawing. Application. September 30, 1957 Serial N0. 686,851.

6 Claims. (Cl. 99-2) particularly poultry admin. The exact mechanism ofthis phenomenon is not understood, but the processhas prov'en to be ofsuflicient value so that certain antibotics are widely used foragricultural purposes. Among the more active antibiotics for use instimulating the growth of poultry is penicillin, which is marketed insuch forms as procaine penicillinor dibenzylethylenediamine penicilline.It has been observed in recent years that the degree of response ofpoultry to penicillin is not as favorable now as it was when'much of thework in this'field was originally done; that is, the rate of growth of,for instance, chicks, on a nutritious diet containing what is normallyconsidered to be an adequate level of penicillin is not as great whencompared to the same type of animals fed on the same type diet withoutthe pencillin as wasencountered five years or more ago. It has beenspeculated that this is due not to a failure of the penicillin to havean effect on the animals growth, but rather that the effect is due tothe absence in the environment of the control animals of microorganismswhich, to some extent, suppress the full growth of these animals. Thismay be due to a greater practice of sanitary techniquesin recent yearsand also to the continued use of antibiotic products in animal feeds.

It has now been found that animal feeds containing nutritional levels ofthe antibiotic, oleandomycin, elicit a substantially greater growthincrease and feed etficiency re-' sponse than any otherantibiotic nowavailable and substantially greater than the responseelicited bypenicillin which, as indicated above, is considered. to be .one of themals inquestion, thelevel may be substantially increased with subsequentcontrol of the infection if it is due ;to an oleandomycin-sensitivestrain of microorganism. Although some effect may be obtained by lessthan 1.0 gram per ton of feed, it may be variable, and it is advisablenot to use appreciably lesser amounts. The preferredpro portion isfromabout one gram'to about five grams of oleandomycin antibioticcompound per ton of feed.

The herein described feeds of this invcntionhave been found to beparticularly valuable and outstanding in the case of non-ruminantanimals, such as chickens, turkeys, ducks, hogsIan'd' the like. Theoleandomycin may, of course, be administered in one component of the'feed or it may be blended uniformly, throughout a mixed feed.Alternatively, it may be administered in an equivalent amount via theanimals water ration or'other fluids. A variety of feed components maybe of use in the, nutritional diets.f A type ofconventional feedmaterial in the case of poultry-,-which is often preferred in theoperation of. this invention, islone which follows generally thesuggested formulae set forth on page six of the authoritative pamphletissued by the National Research Council (Washington, .D.C., June 1944),and entitled Recommended Nutrient Allowances .for Poultry. Forinstance,feed compositions are recommended to containroughly between,50% and 80%of grains, between.3% and 10% of animal protein, between,5% and 30% ofvegetable protein, between 2% and 4% of minerals, together withsupplementary, vitaminaceous sources. I

When reference is made to oleandomycin herein, this term is intended toinclude not only the basic compound itself, butalsotheoleandomycin-chloroform adduct as well as various nontoxic,pharmacologically acceptable acid addition salts, such as thehydrochloride, sulfate,

phosphate, hydrobromide, acetate,citrate and tartrate, etc. It is alsointended to include within this termivarious biologically activederivatives of oleandomycin, such as the lower polyacyl esters ofoleandomycin having from two. to four carbon atoms in the acyl moiety.The procbest of the antibiotics for use in poultry. oleandomycin is acommercially available antibiotic, the production and properties ofwhich are described and claimed in US. Patent No. 2,757,123 by B. A.Sobin et. al. The true nature of the herein described activity, i.e.,the fact that oleandomycin should bringabout an appreciably greaterresponse substantially greate'rthanthe use of as much as I four timesthat quantity of pencillin. In general, olean-' domycin may be used inanimal feeds at a concentration level of from about 1.0 gram to about 40grams per ton aebta th un u l y i -shares aww r w any;,limit tion-pathesnr ther of,

ess for. the production 01: tri-lower acyl esters comprises contactingoleandomycin with the corresponding acyl an-, hydride. This reaction ispreferably conducted in the presence of a basic catalystand an excessofthe acylating agent is usually employed for optimum results. The processcan be suitably conducted at a temperature in the range of from about 0to about 50 C. for a time period of from about five toabout 48 hours.Furthermore, oleandomyciii'm'ay beused in animal feeds in conjunctionwith, various other antibiotics or therapeutic agents such aspenicillin,"oxytetracycline, tetracycline, chlortetracycline,bacitracin, sultaquinoxaline, 'phenylarsonic acid, etc.

- In accordance with a preferred embodiment of this invention, it hasbeen 'found that inv chick battery trials of four'weeksT-fduration, theaddition of oleandomycin to the feed atlevels of one to. five grams perton afiorded growth and feed .efiiciency responses that were two tothree times the magnitude obtainedv with procaine penicillin.Inparticular, the weight'of the chicks is increased by about- 7.-l0% andthefeed efliciency is improved by about 1-3%; comparable levels ofpenicillinincrease'the W y y 04% a m e he f sifi s r only by 0 2Furthermore, these responses to oleandomy cin -con :entratiorif levelsin the f rangeof 'fonr' to live, rams ton areas great ,asathose obtainedwith, higher Qn9 t ti m le s so t e m b ot el- This, inv jtion s furtherillustrated by the xam es; .which ar no to. be, considered s mpo g Ex eThe growth experiments with oleandomycin were conducted on Nicholswhite-cross chicks kept in electrically heated brooders on raised wirefloors. The day old chicks were divided into lots of five males and fivefemales per compartment, replicated twice per treatment. The basal dietemployed is shown below in the following table:

Ingredients Diet (lbs Gro"nd Yellow Corn 56.44 44% Solvated SoybeanMeal. 2 94 Corn Gluten Meal Alfalfa Meal. Stabili-ed Animal Fat DriedCorn Distillers Solubles. Dried Whey (50% delactosed). DriedBre'vers YeIodied Sa t I I Calcium Carbonate Calcium Phosphate, Dibasic Delamix VDL-Methinnine p I Vitamin A (10,000 I.U./g.)- VitaminB Vitamin D; (1500I.C.U./g.l' 7 V Riboflavin DL-Calcium Pantothenate Niacin. CholineChloride 257 N ,N-Diphenyl-phenylenediamine The antibiotic testmaterialswere added to thediet in premix form at the expense of yellowcornmeal. Birds were individually weighed and records of feedconsumption by lot were maintained. Four weekchick weights weresubjected to statistical analysis for significance by the method ofanalytical variance. The results obtained are presented in the followingtable:

Antibiotic, Av. Weight Mortality, Treatment gra ns/ton. (Grams) Bercent2 weeks.

None O 144 1 4 151 0 40 154 0 The above experiment was conducted on tworeplicates of chicks per treatment with both four grams and 40 grams ofoleandomycin per. ton of feed for a period of two weeks. 1

When New Hampshire Red chicks were treated in asimilar manner, theresults obtained were substantially the same.

Examplev II The same procedure as described in Example-I was followedhere except that it was of four weeks duration with four replicates pertreatment. The results obtained are reported in the following table:

' Anti- Av. Weight Feed Eibiotic, (grams) ficiency I Mor- Treatmentgrams/ (Lbs ;Feed/ tality;

ton Lbs. Gain) ,Percent 2 weeks tweeks 4weeks None 161' 364 1. 98Procaine Penicillim- 4 159 358 201 Do 400 177 379 1.97

As illustrated above, it was found that, the, inclusion of four grams ofprocaine penicillin per ton produced no improvement in growth or feedefficiency; but 400 grams of procaine penicillin per ton offeedproduceda small growth response. However, witholeandomycin atfourgramsper ton, growth'andfeed efiiciency were improved over that of thenegative control group-or the-penicillin group. The addition of higherlevel of oleandomycin (40 to 400 grams per ton) did not produce animprovement over results obtained with four grams of this antibiotic.

Example 111 The same procedure as described in Example II was followedhere except that the concentration levels of procaine. penicillin andoleandomycin employed were As illustrated abovelit was found that theinclusion of procaine penicillin at the rate of five or 25 grams per tonproduced only slight, nonsignificant improvements in growth and feedefiiciency. However, equal levels of oleandomycin produced'growthresponses ofapproximate- 1y three times the magnitude obtained withprocaine'penicillin. The superiority of the growth with oleandomycinover that with procaine penicillin was statistically significant.

' Example IV A similar experiment, again conducted with a nutritionallybalanced basalratio but utilizing lower concentration levels ofoleandomycin, was, carried, out for a period .ofifour weeks with thefollowing results:

Antibioti 0,

Av. Weight grams/ton (g 4 weeks Treatment Nnne ProcainePenicillinDBMPHQMHO Example V Maryland Medium White turkey poults were treated inthe manner of. the previous examples with a nutritionallybalanced dietcontaining oleandomycin at a concentrw tion level of.30 grams per ton.of feed. The basal diet employed is presented inv the following table:

Diet (lbs.)

Ingredients Fine Ground Yellow. Corn 44% Solvated Soybean Meal CornGluten Meal Alfalfa Meal 17% Dehyd Stabilized Animal Fat Fish Meal-Dried Corn Distillers' Solubles Dried Whey (50% delaetosed) DriedBrewers Y t Iodized Salt Calcium Carb ate Calcium P ph DplamixDL.M|=thim'\im= Vitamin A-'(l0,000 LIL/g.) Vitamin B m ps pppp prr'prrrm rww$a l" 1 Vitamin D (3,000 I.C.U./g.) 5 Riboflavin DL-Calc'um.Pantothenate 45%.. 1 Niacin" l Choline Chlorid 25% Attheend' of twoweeksitwas found-that the" average birds in'the control group.

Example VI a When triacetyloleandomycin was used in place ofoleandomycin'base in each of the aforesaid examples,

the results obtained were substantially the same. This the-range of fromabout 1.0 gram to about'40lgrams per ton of teed.

2; A feed composition as claimed in claim 1 whereinthe 1 oleandomycinantibioticcompound is oleandomyein base.

3. A feed'composition as claimed in claiml wherein the oleandomycinantibiotic compound is a pharmacologically a acceptable oleandomycinacid addition salt.

was also the case when tripropionyloleandomycin andtributyryloleandomycin were similarly employed. Example -Vll I Whenoleandomycin hydrochloride was mam each of the above examples, theresults obtained were substantially the same as those afiorded byoleandomycinbaser In a similar manner, oleandomycin hydrobromide,cleandomycin hydriodide, oleandomycin phosphate, oleando- 4. A feedcomposition as claimed inclaim 1 wherein the oleandomycin antibioticcompound is a lower aliphatic polyacyl ester of oleandomycin havingfromtwo to four rcarbonatoms in the acyl moiety.

7 to a nutritionallybalanced feed composition containing r mycinsulfate, oleandomycin acetate,'oleandomycin citrate and oleandomycintartrate were all individually em ployed in lieu of oleandomycin base;in each case, the results obtained were in substantial agreement withthe data obtained in the previousexamples.

Hence, this invention provides new and useful animal 1 feeds containingoleandomycin antibiotics whichafiord a truly remarkable magnitude ofgrowth respo n'ses-in view I of the difiiculty usually encountered inobtaining antibiotic responses under battery conditions.

What is claimed is: 1 l I l- 1. .An animal feed composition comprising anutritionally-balanced animal feed together with an oleandomycinantibiotic compound at a concentration level that in 5. A'process forincreasing growth and improvingfeed efliciency in animals whichcomprises administering therefrom about 1.0 gram to about 40 gramsproportion of an oleandomycin antibiotic compound per ton of feedcomposition.

6. A process for-increasing growth and improving feed e'fiiciency innon-ruminant animals, whichprocess' comprises feeding these animals onanutritionally balanced feed compostion containing from about 1.0 gram toabout 40' grams prop'ortionof an oleandomycin antibiotic coma pound perton of feed composition.

I References Citedin the file of this patent Braude et' al.: Antibiotics& Chemotherapy, July 1953,

' .vol; '3, pp. 271- 285.

Sobin et al.: Antibiotic Annual, 1954-195 5, pp.'827- 830; MedicalEncyclopedia Inc., NY.

1. AN ANIMAL FEED COMPOSITION COMPRISING A NUTRITIONALLY-BALANCED ANIMALFEED TOGETHER WITH AN OLEANDOMYCIN ANTIBIOTIC COMPOUND AT ACONCENTRATION LEVEL THAT IS IN THE RANGE OF FROM ABOUT 1.0 GRAM TO ABOUT40 GRAMS PER TON OF FEED.